Delphinidin inhibits retinal photochemical damage by regulating the cGAS-STING pathway to suppress NCOA4-mediated ferritinophagy.

UCHL1 attenuates diabetic retinopathy by deubiquitinating and stabilizing NRF2 to suppress oxidative stress-induced retinal vascular endothelial ferroptosis.

Diabetic retinopathy (DR) is characterized by progressive retinal microvascular injury, with oxidative stress and ferroptosis increasingly recognized as key pathogenic contributors. This study investigated whether ubiquitin C-terminal hydrolase L1 (UCHL1) regulates retinal endothelial ferroptosis through stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Analysis of the GSE102485 dataset identified UCHL1 as a downregulated deubiquitinating enzyme in DR. Streptozotocin-induced type 1 diabetic mice and high glucose (HG)-induced human retinal capillary endothelial cells (HRCECs) were used, together with UCHL1 inhibition/knockdown, AAV-mediated UCHL1 overexpression, and NRF2 knockdown. UCHL1 expression was reduced in diabetic retinas and HG-induced HRCECs, accompanied by ferroptosis activation, mitochondrial injury, and endothelial dysfunction. Pharmacological inhibition or siRNA-mediated depletion of UCHL1 intensified oxidative stress, Fe2⁺ accumulation, lipid peroxidation, mitochondrial fragmentation, and cristae disruption, while impairing endothelial barrier integrity, migration, and tube formation. In vivo, LDN57444 aggravated retinal vascular leakage and fundus vascular abnormalities, whereas AAV-UCHL1 preserved retinal architecture and reduced vascular permeability. Mechanistically, co-immunoprecipitation and ubiquitination assays demonstrated that UCHL1 interacted with NRF2 and stabilized NRF2 by removing K48-linked polyubiquitin chains. Nuclear-cytoplasmic fractionation further showed that UCHL1 overexpression restored NRF2 abundance and increased nuclear NRF2 accumulation under HG conditions. Ferrostatin-1 rescued UCHL1 depletion-induced ferroptotic injury, whereas NRF2 knockdown abolished the protection conferred by UCHL1 overexpression. These findings highlight the UCHL1/NRF2 axis may represent a therapeutic target in DR.

Epigallocatechin gallate protects ARPE-19 cells in vitro and the retina in vivo by suppressing NF-κB p65-mediated ferroptosis.

The accumulation of ferrous ions and resulting oxidative stress within the retinal pigment epithelium triggers ferroptosis, leading to photoreceptor degeneration in dry age-related macular degeneration (dAMD), which is a disease currently without effective therapy. As ferroptosis has been identified as a molecular target of epigallocatechin-3-gallate (EGCG) in other diseases, this study aimed to investigate the protective role of EGCG and its mechanism against ferroptosis in NaIO3-induced ARPE-19 cell and RPE injury. We observed that iron overload disrupts iron homeostasis in both cellular and animal models, leading to RPE damage via ferroptosis activation. In ARPE-19 cells, EGCG attenuated NaIO3-induced injury by reducing Fe2+, MDA, and LDH levels, increasing GSH content, and upregulating SLC7A11 and GPX4 expression, effects which were equivalent to those produced by Fer-1. Mechanistically, EGCG exerted its anti-ferroptotic effect by binding strongly to NF-κB p65 and inhibiting its activation, consistent with the effects of the NF-κB inhibitor QNZ and NF-κB p65 silencing. In a dAMD model, EGCG administration suppressed ferroptosis, downregulated NF-κB p65 expression, and ameliorated RPE damage. In conclusion, these findings suggest that EGCG alleviates RPE damage associated with NF-κB p65-mediated ferroptosis, providing new insights into AMD pathogenesis and a promising therapeutic strategy.

Procyanidin C1 modulates microglia cellular iron homeostasis via targeting HuR/ACSL4 pathway and alleviates high-glucose-induced ferroptosis in diabetic retinopathy.

Diabetic retinopathy (DR), one of the most prevalent microvascular complications of diabetes, is a vision-threatening ocular disease. Although ferroptosis has been implicated in DR development, research on its underlying mechanisms and targeted therapeutics remains limited. Procyanidins, a class of polyphenolic compounds, exhibit robust anti-inflammatory properties and regulatory effects on various pathological processes. Herein, we investigated the potential role of the RNA-binding protein human antigen R (HuR) in mediating ferroptosis during DR progression, as well as the protective effects of Procyanidin C1 (PC1). Streptozotocin-induced diabetic mice and high-glucose-exposed BV2 microglial cells (BV2s) were treated with PC1 to evaluate oxidative stress and the expression of ferroptosis markers. The interaction between HuR and ACSL4 was characterized using ribonucleoprotein (RNP) immunoprecipitation (IP) and mRNA stability assays. Our results demonstrated that PC1 significantly alleviated oxidative stress and ferroptosis in both diabetic mice and high-glucose-treated BV2s. Mechanistically, post-transcriptional regulation by HuR via stabilizing Acsl4 mRNA contributes to the acceleration of ferroptosis during DR progression. Ultimately, PC1 suppresses DR advancement by targeting the HuR-ACSL4 signaling axis, highlighting its potential as a therapeutic intervention.

Ginkgo Biloba Standardized Extract EGb 761 Reduces Light and Toxin-Induced Photoreceptor Cell Damage via Regulating Oxidative Stress and Autophagy.

EGb 761 exerts a protective effect on photoreceptor cell damage in retinal degeneration and is associated with a modification of the AMPK/ERK signaling pathway that regulates oxidative stress and autophagy.

Eugenol regulates ferroptosis through Mfn2/SLC7A11/GPX4 pathway to alleviate glutamate excitotoxicity damage in glaucoma.

FTO/EFNB2 Axis Protects Retinal Ganglion Cells Against H2O2-Induced Oxidative Damage

Background: Traumatic optic neuropathy (TON) causes progressive retinal ganglion cell (RGC) loss and oxidative injury, leading to visual dysfunction. Ephrin B2 (EFNB2) is elevated in optic nerve injury; however, it is unclear how the fat mass and obesity-associated gene (FTO) regulates it upstream. This study examined whether RGCs are shielded from hydrogen peroxide (H2O2)-induced oxidative damage through FTO-mediated EFNB2 overexpression.Methods: Primary RGCs were isolated and exposed to H2O2 to establish an in vitro oxidative stress injury model. We first verified the concentration-dependent induction of FTO and EFNB2 by H2O2. Gain- and loss-of-function assays were performed using FTO overexpression and knockdown plasmids to assess its effects on RGC viability, apoptosis, reactive oxygen species (ROS) accumulation, caspase-3 activity, and the expression of EFNB2, erythropoietin-producing hepatoma receptor B4 (EPHB4) and apoptosis-related proteins. Rescue experiments with EFNB2 knockdown were further conducted to confirm whether EFNB2 acts as a downstream effector of FTO.Results: H2O2 treatment elevated FTO and EFNB2 expression in RGCs in a concentration-dependent manner (p < 0.01). FTO overexpression alleviated H2O2-induced reductions in cell viability, as well as increases in apoptosis, caspase-3 activation, and ROS levels (p < 0.001), while FTO knockdown exacerbated these injuries (p < 0.001). Moreover, FTO overexpression enhanced EFNB2 and EPHB4 expression, and suppressed Bax and cleaved caspase-3 levels (p < 0.001). Knockdown of EFNB2 reversed the protective effects of FTO overexpression on RGC survival, oxidative stress, and apoptosis (p < 0.001).Conclusions: FTO upregulates EFNB2 and EPHB4 expression, reduces ROS and apoptosis, and is associated with the protection of RGCs against H2O2-induced oxidative damage. The FTO/EFNB2 axis may represent a protective mechanism against oxidative damage in RGCs in vitro, warranting further investigation in traumatic optic neuropathy models.